Carbon substituted aminothiazole inhibitors of cyclin dependent kinases

ABSTRACT

Compounds of the formula                    
     and pharmaceutically acceptable salts thereof are provided.

This application claims priority benefit under Title 35 §119(e) ofUnited States Provisional Application No. 60/089,747, filed Jun. 18,1998, and entitled Carbon Substituted Aminothiazole Inhibitors of CyclinDependent Kinases, the entire contents of which are incorporated hereinby reference.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula

and pharmaceutically acceptable salts thereof. As used in formula I, andthroughout the specification, the symbols have the following meanings:

R¹=R², COR³, CONH₂, CONR²R³, COOR², or SO₂R²;

R²=alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl,heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl;

R³=H, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl,heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl;

R⁴=alkyl with two or more carbon atoms, cycloalkyl, heterocycloalkyl,cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, or R⁹, with the proviso that when R¹ is acetyl orpropionyl and

Y=alkene, then R⁴cannot be nitrofuryl or 2-quinolinyl;

R⁵, R⁶, R⁷, R⁸=independently H, alkyl, cycloalkyl, heterocycloalkyl,cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, halo, or

hydroxy, alkoxy, amino, NR¹²R¹³, thio, or alkylthio, with the provisothat only one such heteroatom group is bonded to any one carbon atom;

R¹⁰, R¹¹=independently H, alkyl, cycloalkyl, heterocycloalkyl,cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, halo, hydroxy, alkoxy, alkylcarbonyloxy, carboxy,alkyloxycarbonyl, amino, NR⁵R¹⁶, carbamoyl, ureido, thio, or alkylthio;

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶=independently H, alkyl, cycloalkyl,heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl.

The compounds of formula I are protein kinase inhibitors and are usefulin the treatment of proliferative diseases, for example, cancer,inflammation and arthritis. They may also be useful in the treatment ofAlzheimer's disease, and cardiovascular disease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows compounds represented by Examples 7-14.

FIG. 2 shows compounds represented by Examples 15-25.

FIG. 3 shows compounds represented by Examples 26-34.

FIG. 4 shows compounds represented by Examples 35-44.

FIG. 5 shows compounds represented by Examples 45-56.

FIG. 6 shows compounds represented by Examples 57-63.

FIG. 7 shows compounds represented by Examples 64-72.

FIG. 8 shows compounds represented by Examples 73-81.

FIG. 9 shows compounds represented by Examples 82-90.

FIG. 10 shows compounds represented by Examples 91-99.

FIG. 11 shows compounds represented by Examples 100-109.

FIG. 12 shows compounds represented by Examples 110-119.

FIG. 13 shows compounds represented by Examples 120-128.

FIG. 14 shows compounds represented by Examples 129-132.

FIG. 15 shows compounds represented by Examples 133-140.

FIG. 16 shows compounds represented by Examples 141-150.

FIG. 17 shows compounds represented by Examples 151-160.

FIG. 18 shows compounds represented by Examples 161-171.

FIG. 19 shows compounds represented by Examples 172-183.

FIG. 20 shows compounds represented by Examples 184-189.

DESCRIPTION OF THE INVENTION

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds, and for methods ofusing such compounds.

Listed below are definitions of various terms used to describe thecompounds of the instant invention. These definitions apply to the termsas they are used throughout the specification (unless they are otherwiselimited in specific instances) either individually or as part of alarger group.

It should be noted that any heteroatom with unsatisfied valances isassumed to have the hydrogen atom to satisfy the valances.

Carboxylate anion refers to a negatively charged group —COO⁻.

The term “alkyl” or “alk” refers to a monovalent alkane (hydrocarbon)derived radical containing from 1 to 12 carbon atoms unless otherwisedefined. An alkyl group is an optionally substituted straight, branchedor cyclic saturated hydrocarbon group. When substituted, alkyl groupsmay be substituted with up to four substituent groups, R as defined, atany available point of attachment. When the alkyl group is said to besubstituted with an alkyl group, this is used interchangeably with“branched alkyl group”. Exemplary unsubstituted such groups includemethyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.Exemplary substituents may include but are not limited to one or more ofthe following groups: halo (such as F, Cl, Br, I), haloalkyl (such asCCl₃ or CF₃), alkoxy, alkylthio, hydroxy, carboxy (—COOH),alkyloxycarbonyl (—COOR), alkylcarbonyloxy (—OCOR), amino (—NH₂),carbamoyl (—NHCOOR— or —OCONHR—) urea (—NHCONHR—), amidinyl (—CNHNHR or—CNRNH₂), or thiol (—SH). Alkyl groups as defined may also comprise oneor more carbon to carbon double bonds or one or more carbon to carbontriple bonds.

The term “alkenyl” refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 12 carbon atoms and at least one carbon tocarbon double bond.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 12 carbon atoms and at least one carbon tocarbon triple bond.

Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms,without alternating or resonating double bonds between carbon atoms. Itmay contain from 1 to 4 rings. Exemplary unsubstituted such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Exemplarysubstituents include one or more of the follow ng groups: halogen,alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and/oralkylthio.

The terms “alkoxy” or “alkylthio”, as used herein, denote an alkyl groupas described above bonded through an oxygen linkage (—O—) or a sulfurlinkage (—S—), respectively.

Sulfoxide and sulfone denote groups bonded by —SO— or —SO₂— linkages,respectively.

The term “alkyloxycarbonyl”, as used herein, denotes an alkoxy groupbonded through a carbonyl group. An alkoxycarbonyl radical isrepresented by the formula: —C(O)OR, where the R group is a straight orbranched C₁₋₆, alkyl group.

The term “alkylcarbonyl” refers to an alkyl group bonded through acarbonyl group.

The term “alkylcarbonyloxy”, as used herein, denotes an alkylcarbonylgroup which is bonded through an oxygen linkage.

The term “arylalkyl”, as used herein, denotes an aromatic ring bonded toan alkyl group as described above.

The term “aryl” refers to monocyclic or bicyclic aromatic rings, e.g.phenyl, substituted phenyl and the like, as well as groups which arefused, e.g., napthyl, phenanthrenyl and the like. An aryl group thuscontains at least one ring having at least 6 atoms, with up to five suchrings being present, containing up to 22 atoms therein, with alternating(resonating) double bonds between adjacent carbon atoms or suitableheteroatoms. Aryl groups may optionally be substituted with one or moregroups including, but not limited to halogen, alkyl, alkoxy, hydroxy,carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino,cycloalkyl, cyano, alkyl S(O)_(m) (m=O, 1, 2), or thiol.

The term “heteroaryl” refers to a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10atoms, containing at least one heteroatom, O, S, or N, in which a carbonor nitrogen atom is the point of attachment, and in which one or twoadditional carbon atoms is optionally replaced by a heteroatom selectedfrom O or S, and in which from 1 to 3 additional carbon atoms areoptionally replaced by nitrogen heteroatoms, said heteroaryl group beingoptionally substituted as described herein. Exemplary heteroaryl groupsinclude the following: thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl,pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyrazinyl, tetrazolyl, pyridazinyl,pyrimidinal, triazinylazepinyl, indolyl, isoindolyl, quinolinyl,isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl,benzoxadiazolyl, benzofurazanyl and tetrahydropyranyl. Exemplarysubstituents include one or more of the following: halogen, alkyl,alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, trifluoromethyl,cycloalkyl, nitro, cyano, amino, alkylS(O)_(m) (m=0, 1, 2), or thiol.

The term “heteroarylium” refers to heteroaryl groups bearing aquaternary nitrogen atom and thus a positive charge.

The term “heterocycloalkyl” refers to a cycloalkyl group (nonaromatic)in which one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S or N, and in which up to three additional carbonatoms may be replaced by said heteroatoms.

The term “quaternary nitrogen” refers to a tetravalent positivelycharged nitrogen atom including, e.g. the positively charged nitrogen ina tetraalkylammonium group (e.g. tetramethylammonium,N-methylpyridinium), the positively charged nitrogen in protonatedammonium species (e.g. trimethylhydroammonium, N-hydropyridinium), thepositively charged nitrogen in amine N-oxides (e.g.N-methyl-morpholine-N-oxide, pyridine -N-oxide), and the positivelycharged nitrogen in an N-amino-ammonium group (e.g. N-aminopyridinium).

The term “heteroatom” means O, S or N, selected on an independent basis.

The term “halogen” or “halo” refers to chlorine, bromine, fluorine oriodine.

When a functional group is termed “protected”, this means that the groupis in modified form to preclude undesired side reactions at theprotected site. Suitable protecting groups for the compounds of thepresent invention will be recognized from the present application takinginto account the level of skill in the art, and with reference tostandard textbooks, such as Greene, T. W. et al., Protective Groups inOrganic Synthesis, Wiley, N.Y. (1991).

Suitable examples of salts of the compounds according to the inventionwith inorganic or organic acids are hydrochloride, hydrobromide,sulfate, phosphate. Salts which are unsuitable for pharmaceutical usesbut which can be employed, for example, for the isolation orpurification of free compounds I or their pharmaceutically acceptablesalts, are also included.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The definition of the compounds according to the invention embraces allpossible stereoisomers and their mixtures. It very particularly embracesthe racemic forms and the isolated optical isomers having the specifiedactivity. The racemic forms can be resolved by physical methods, suchas, for example, fractional crystallization, separation orcrystallization of diastereomeric derivatives or separation by chiralcolumn chromatography. The individual optical isomers can be obtainedfrom the racemates by conventional methods, such as, for example, saltformation with an optically active acid followed by crystallization.

All configurational isomers of compounds of the present invention arecontemplated, either in admixture or in pure or substantially pure form.The definition of compounds of the present invention very particularlyembraces both cis (Z) and trans (E) alkene isomers, as well as cis andtrans isomers of cycloalkyl or heterocycloalkyl rings.

It should be understood that solvates (e.g. hydrates) of the compoundsof formula I are also within the scope of the present invention. Methodsof solvation are generally known in the art. Accordingly, the compoundsof the instant invention may be in the free or hydrate form, and may beobtained by methods exemplified by the following schemes.

The synthesis of compounds of formula I can proceed through the knownaldehyde of formula II (Scheme 1) which was prepared according to theprocedures set forth in II Farmaco 44, 1011, (1989) and the referencestherein. Treatment of II with either (R²CO)₂O or R¹—L, where L is aleaving group such as a halogen or sulfonate ester, yields compounds offormula III. Condensation of formula III with phosphorus-stabilizedanions such as the phosphonate of formula IV or a Wittig reagent in thepresence of base yields compounds of formula V (that is, compounds offormula I where A contains an alkene present as either the cis or transisomer). Alternatively, compounds of formula V may be prepared by firstreacting formula II with the phosphonate of formula IV or a Wittigreagent in the presence of base, and then treating the resulting productwith (R²CO)₂O or R¹—L.

Compounds of formula V may be converted into other compounds of formulaI as shown in Scheme 2. For example, treatment of compounds of formula Vwith agents such as H₂ on Pd/C yields the saturated compounds of formulaVI (which is a compound of formula I. Alternatively compounds of formulaV may be epoxidized with agents such as dimethyldioxirane orm-chloroperbenzoic acid to yield epoxides of formula VII (which arecompounds of formula I where Y=the carbon atoms of oxirane).Cyclopropanation of the olefin with agents such as ZnCuCH₂ ordiazomethane may yield cyclopropanes of formula VIII (which arecompounds of formula I where Y=cyclopropane).

Aldehydes of formula III may also be converted into compounds of formulaI which have R⁷ or R⁸ groups containing oxygen (Scheme 3). For example,addition of organometallic reagents of formula R*—M, where R*13=R⁴(R⁵R⁶C)_(i)— or R⁴(R⁵R⁶C)_(i)—Y— and M=a metal, would yield compoundsof formula IX (that is, compounds of formula I where R⁷=hydroxy andR⁸=H). Alkylation of the hydroxyl group in compounds of formula IX usingW—L, where W=alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl,heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl,and L is a leaving group such as a halogen or sulfonate ester, wouldyield ethers of formula X (that is, compounds of formula I withR⁷=alkoxy).

Scheme 4 outlines a procedure that may be used for the solid phasesynthesis of compounds of formula I. A benzyl chloride resin, such asthat depicted by formula XII, may be alkylated by an aminothiazole offormula III (where R¹=CF₃CO) to give a compound of formula XII. Couplingwith phosphorus stabilized anions such as compounds of formula IV willyield alkenes of formula XIII which may be deprotected by a reducingagent such as sodium borohydride, or a base such as sodium hydroxide, togive amines of formula XIV. The amines of formula XIV may react withR¹—L or (R²CO)₂O to give compounds of formula XV, which may be cleavedfrom the resin with trifluoroacetic acid to give compounds of formula V(which are compounds of formula I where Y is an alkene). Compounds offormula IX or X may also be synthesized on solid phase using analogouschemistry to that shown in Scheme 3 by starting with aldehyde XII.

Compounds of formula I wherein R⁴=R⁹ may be synthesized from aldehydesof formula III (Scheme 5). These aldehydes may be reduced with agentssuch as sodium borohydride to give alcohols of formula XVI which may beconverted into a compound of formula XVII, where L is a leaving groupsuch as a halogen or sulfonate ester, by treatment with agents such asp-toluenesulfonyl chloride and base or thionyl chloride. The anion ofdialkylmalonate esters of formula XVIII may be alkylated by compounds offormula XVII to form diesters of formula XIX, where W=alkyl, cycloalkyl,heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl. These diesters may besaponified and decarboxylated to form acids of formula XX which may becoupled with amines of formula XXI to give amides of formula XXII. Theseamides may be cyclized upon exposure to dehydrating agents such asPOCl₃to form compounds of formula VI which are compounds of formula Iwhere Z=O.

Compounds of formula I wherein R4=R9 and Y=alkynyl or Z-alkenyl may beprepared from halomethyl oxazoles such as XXIII (Scheme 6). Displacementof the chlorine to give the acetate XXIV, followed by basic hydrolysisand oxidation provides a 2-oxazolylaldehyde XXVI. The aldehyde may betreated with a reagent such as carbon tetrabromide andtriphenylphosphine to give a dibromo olefin XXVII. Elimination of HBr bystrong base, followed by lithiation and quenching the acetylenic anionwith tributyltin chloride gives an acetylenic stannane XXVIII, which maybe coupled with a 2-iodo aminothiazole XXIX, to give XXX, which is acompound of formula I wherein R⁴=R⁹and Y is alkynyl. The acetyleniccompounds of formula XXX may be hydrogenated to provide cis olefins XXXIand XXXIII, which are compounds of formula I wherein R⁴=R⁹ and Y isZ-alkenyl.

Compounds of formula I wherein R1=R2 may be prepared by the methodsshown in Scheme 7. 5-Formyl-2-aminothiazole II is reacted with anitrosating agent such as tBuONO and CuBr2 to form the 2-bromoderivative XXXIV. Following procedures as described in Scheme I, thealdehyde is reacted with a phosphonate of formula IV or a Wittig reagentin the presence of base to provide an olefin of formula XXXV. Reactionof the 2-bromo olefin of formula XXXV with a compound of formula R2NH2in the presence of a base such as sodium hydride gives compounds offormula, which is a compound of formula I wherein R1=R2 and Y isalkenyl.

Alternatively, compounds of formula XXXVI where R¹=R² and Y is alkenylmay be prepared according to Scheme 8. The amino group of compound IImay be protected with a reagent such as di-t-butyl dicarbonate to giveXXXVII, followed by reaction with a phosphonate of formula IV or aWittig reagent in the presence of base such as an alkoxide or sodiumhydride to give a compound of formula XXXVIII. Treatment of XXXVIII withR²L where L is a leaving group such as halo or sulfonate, in thepresence of base, followed by removal of the protecting group gives acompound of formula XXXVI, which is a compound of formula I where R¹=R²and Y is alkenyl.

Compounds of formula R⁴CH₂P(O)(OEt)₂ may be prepared from compounds offormula R⁴CH₂L, where L is a leaving group such as halogen or sulfonateester, by heating with triethylphosphite. Compounds of formula R⁹—L,where Z=O, may be prepared from LCH₂CN and R¹¹C(N₂)COR¹⁰, according topart E of Example 2.

The starting compounds of Schemes 1-7 are commercially available or maybe prepared by methods known to one of ordinary skill in the art.

All compounds of formula I may be prepared by modification of theprocedures described herein.

Preferred compounds of formula I are those where:

R¹=R², COR³, or CONR²R³;

R²=alkyl, aryl, or heteroaryl;

R³=H, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;

R⁴=alkyl with two or more carbon atoms, aryl, heteroaryl, or R⁹;

R⁵, R⁶, R⁷, R⁸=independently H, or alkyl;

R¹⁰, R¹¹=independently H, or alkyl.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of formula I are inhibitors ofprotein kinases such as the cyclin dependent kinases (cdks), forexample, cdc2 (cdk1), cdk2, and cdk4. The novel compounds of formula Iare expected to be useful in the therapy of proliferative diseases suchas cancer, inflammation, arthritis, Alzheimer's disease andcardiovascular disease. These compounds may also be useful in thetreatment of topical and systemic fungal infections.

More specifically, the compounds of formula I are useful in thetreatment of a variety of cancers, including (but not limited to) thefollowing:

carcinoma, including that of the bladder, breast, colon, kidney, liver,lung, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin;

hematopoietic tumors of lymphoid lineage, including acute lymphocyticleukemia, B-cell lymphoma, and Burkett's lymphoma;

hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias and promyelocytic leukemia;

tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma; and

other tumors, including melanoma, seminoma, teratocarcinoma,osteosarcoma, neuroblastoma and glioma.

Due to the key role of cdks in the regulation of cellular proliferationin general, inhibitors could act as reversible cytostatic agents whichmay be useful in the treatment of any disease process which featuresabnormal cellular proliferation, e.g., neuro-fibromatosis,atherosclerosis, pulmonary fibrosis, arthritis, psoriasis,glomerulonephritis, restenosis following angioplasty or vascularsurgery, hypertrophic scar formation, inflammatory bowel disease,transplantation rejection, angiogenesis, and endotoxic shock.

Compounds of formula I may also be useful in the treatment ofAlzheimer's disease, as suggested by the recent finding that cdk5 isinvolved in the phosphorylation of tau protein (J. Biochem, 117, 741-749(1995)).

Compounds of formula I may also act as inhibitors of other proteinkinases, e.g., protein kinase C, her2, rafl, MEK1, MAP kinase, EGFreceptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src,AbI, and thus be effective in the treatment of diseases associated withother protein kinases.

The compounds of this invention may also be useful in combination withknown anti-cancer treatments such as radiation therapy or withcytostatic and cytotoxic agents, such as for example, but not limitedto, DNA interactive agents, such as cisplatin or doxorubicin; inhibitorsof farnesyl protein transferase, such as those described in pending U.S.application Ser. No. 08/802,239 which was filed on Feb. 20, 1997;topoisomerase II inhibitors, such as etoposide; topoisomerase Iinhibitors, such as CPT-11 or topotecan; tubulin stabilizing agents,such as paclitaxel, docetaxel or the epothilones; hormonal agents, suchas tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil;and antimetabolites, such as methoxtrexate; antiangiogenic agents, suchas angiostatin; and kinase inhibitors, such as her2 specific antibodies.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent within its approved dosagerange. For example, the cdc2 inhibitor olomucine has been found to actsynergistically with known cytotoxic agents in inducing apoptosis (J.Cell Sci., 108, 2897 (1995)). Compounds of formula I may be usedsequentially with known anti-cancer or cytotoxic agents when acombination formulation is inappropriate.

cdc2/cyclin B1 Kinase Assay

cdc2/cyclin B1 kinase activity was determined by monitoring theincorporation of ³²P into histone HI. The reaction consisted of 50 ngbaculovirus expressed GST-cdc2, 75 ng baculovirus expressed GST-cyclinB1, 1 μg histone HI (Boehringer Mannheim), 0.2 μCi of ³²P γ-ATP and 25μM ATP in kinase buffer (50 mM Tris, pH8.0, 10 mM MgCl₂, 1 mM EGTA, 0.5mM DTT). The reaction was incubated at 30° C. for 30 minutes and thenstopped by the addition of cold trichloroacetic acid (TCA) to a finalconcentration of 15% and incubated on ice for 20 minutes. The reactionwas harvested onto GF/C unifilter plates (Packard) using a PackardFiltermate Universal harvester, and the filters were counted on aPackard TopCount 96-well liquid scintillation counter (Marshak, D. R.,Vanderberg, M. T., Bae, Y. S., Yu, I. J., J. of Cellular Biochemistry,45, 391-400 (1991), incorporated by reference herein).

cdk2/cyclin E Kinase Assay

cdk2/cyclin E kinase activity was determined by monitoring theincorporation of 3²P into the retinoblastoma protein. The reactionconsisted of 2.5 ng baculovirus expressed GST-cdk2/cyclin E, 500 ngbacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 μCi³²P γ-ATP and 25 μM ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mMMgCl₂, 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30° C. for 30minutes and then stopped by the addition of cold trichloroacetic acid(TCA) to a final concentration of 15% and incubated on ice for 20minutes. The reaction was harvested onto GF/C unifilter plates (Packard)using a Packard Filtermate Universal harvester, and the filters werecounted on a Packard TopCount 96-well liquid scintillation counter.

cdk 4/cyclin D1 Kinase Activity

cdk4/cyclin D1 kinase activity was determined by monitoring theincorporation of ³²P in to the retinoblastoma protein. The reactionconsisted of 165 ng baculovirus expressed as GST-cdk4, 282 ngbacterially expressed as S-tag cyclin D1, 500 ng bacterially producedGST-retinoblastoma protein (aa 776-928), 0.2 μCi ³²P γ-ATP and 25 μM ATPin kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl₂, 5 mM EGTA, 2 mMDTT). The reaction was incubated at 30° C. for 1 hour and then stoppedby the addition of cold trichloroacetic acid (TCA) to a finalconcentration of 15% and incubated on ice for 20 minutes. The reactionwas harvested onto GF/C unifilter plates (Packard) using a PackardFiltermate Universal harvester, and the filters were counted on aPackard TopCount 96-well liquid scintillation counter (Coleman, K. G.,Wautlet, B. S., Morissey, D, Mulheron, J. G., Sedman, S., Brinkley, P.,Price, S., Wedster, K. R. (1997) Identification of CDK4 Sequencesinvolved in cyclin D, and p16 binding. J. Biol. Chem.272,30:18869-18874, incorporated by reference herein).

The following examples and preparations describe the manner and processof making and using the invention and are illustrative rather thanlimiting. It should be understood that there may be other embodimentswhich fall within the spirit and scope of the invention as defined bythe claims appended hereto.

EXAMPLE 1 Ethyl 3-((E)-2-acetamido-thiazol-5-yl)-acrylate

A. Preparation of 2-acetamido-5-bromothiazole

To a solution of 2-amino-5-bromothiazole (22.3 g, 85.9 mmol) inmethylene chloride (100 mL) and pyridine (60 mL) was added aceticanhydride (11 mL) slowly with stirring. The mixture was allowed to stirfor 2.5 hours, warmed to room temperature, and stirred for an additional4 hours. Most of the solvent was removed in vacuo and the residue waswashed with ethyl acetate and aqueous HCl. The organic solution was thenwashed with water, dried over MgSO₄ and concentrated to give a crudesolid. This solid was triturated with Et₂O, filtered, washed with Et₂O,and dried to give 2-acetamido-5-bromothiazole as a solid (15.1 g, 80%,C₅H₅BrN₂OS, MS m/e 222 (M+H)⁺).

B. Preparation of ethyl 3-((E)-2-acetamido-thiazol-5-yl)-acrylate

A mixture of acetamido-5-bromothiazole (440 mg, 2.0 mmol), ethylacrylate (400 mg, 4 mmol) and triethylamine (3 mL) in DMF (3 mL) wasstirred at 90° C. under argon in the presence of Pd(tol₃P)₂Cl₂ (150.0mg) for 24 h. The mixture was concentrated and the residue was dissolvedin methylene chloride (100 mL), washed with water and dried over MgSO₄.The solution was concentrated and the residue was purified by columnchromatography (SiO₂, CH₂Cl₂:MeOH/100:5) to afford ethyl3-((E)-2-acetamido-thiazol-5-yl)-acrylate (100 mg, 21%) as a solid (m.p.239-240° C., C₁₀H₁₂N₂O₃S, MS m/e 240.9 (M+H)⁺).

EXAMPLE 2N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide

A. Preparation of 2-amino-thiazol-5-ylcarboxaldehyde

2-Amino-thiazol-5-ylcarboxaldehyde was synthesized according to theprocedure set forth in II Farmaco 44, 1011, (1989) and the referencestherein.

B. Preparation of 2-acetamido-thiazol-5-ylcarboxaldehyde

To a suspension of 2-amino-thiazol-5-ylcarboxaldehyde (5.0 g, 39 mmol)in toluene (500 mL) was added acetic anhydride (11.0 mL, 117 mmol). Themixture was heated to 110° C. for 5 hours. Upon cooling to roomtemperature, a solid precipitated out of the solution. The reactionmixture was concentrated under vacuum to give2-acetamido-thiazol-5-ylcarboxaldehyde as a light brown colored solid(6.5 g, 98%, C₆H₆N₂O₂S, MS m/e 171 (M+H)⁺).

C. Preparation of diazomethane

Caution: diazomethane is potentially explosive. Care should be taken touse plastic containers, or glassware free of scratches. Solid KOH (60 g)was dissolved in water to make 150 mL of a 40%/o KOH solution. Thissolution was cooled at 0° C. and ether (500 mL) was added. To thiscooled mixture was added 1-methyl-3-nitro-1-nitrosoguanidine (50 g, 0.34mol) in portions over 45 minutes. After addition was complete, the etherlayer was decanted and to give a solution of diazomethane which was useddirectly.

D. Preparation of 1-diazo-3,3-dimethyl-2-butanone

To the diazomethane solution was added a solution of trimethylacetylchloride (15 mL, 0.12 mol) in ether (100 mL) dropwise over 40 minutes.After addition was complete, the solution was allowed to warm slowlyovernight to room temperature. The solution was purged with a flow ofnitrogen gas to remove any excess diazomethane and the resultingsolution was concentrated to give 1-diazo-3,3-dimethyl-2-butanone as ayellow oil which was used directly in the next step.

E. Preparation of 2-(chloromethyl)-5-t-butyloxazole

To a stirred solution of chloroacetonitrile (40 mL) and borontrifluoride etherate (20 mL, 0.16 mmol) at 0° C. was added1-diazo-3,3-dimethyl-2-butanone in chloroacetonitrile (40 mL) dropwiseover a period of 20 minutes. After addition was complete, the mixturewas stirred at 0° C. for one hour and then partitioned between saturatedNaHCO₃ solution (700 mL) and CH₂Cl₂ (500 mL). The aqueous solution was.extracted with CH₂Cl₂ (500 mL) and the combined organic layers werewashed with brine (400 mL) and dried over MgSO₄. After filtration, thesolution was concentrated and then distilled under vacuum using an oilbath temperature of 40° C. The 2-(chloromethyl)-5-t-butyloxazole (9.2 g,44% overall from the acid chloride, C₈H₁₂CINO, MS m/e 174 (M+H)⁺) wasobtained as a light yellow oil.

F. Preparation of (5-t-butyl-oxazol-2-ylmethyl)-phosphonic acid diethylester

A solution of 2-(chloromethyl)-5-t-butyloxazole (8.00 g, 46.1 mmol) intriethylphosphite (15.3 g, 92.0 mmol) was heated at 120° C. for 18hours. After cooling the mixture to room temperature, toluene (30 mL)was added and the solution was concentrated in vacuo with a bathtemperature of 70° C. This procedure was repeated three times and theresulting brown oil was dried in vacuo at 90° C. for 30 minutes to give(5-t-butyl-oxazol-2-ylmethyl)-phosphonic acid diethyl ester (12.4 g,98%, C₁₂H₂₂NO₄P, MS m/e 276 (M+H)⁺) as a red-orange liquid.

G. Preparation ofN-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide

To a solution of (5-t-butyl-oxazol-2-ylmethyl)-phosphonic acid diethylester (195 mg, 0.708 mmol) in tetrahydrofuran (10 mL) was addedpotassium t-butoxide (2.2 mL, 1 M in. THF) via syringe. After 10minutes, a solution of 2-acetamido-thiazo-5-ylcarboxaldehyde (100 mg,0.587 mmol) in THF (6 mL) was added via syringe. Over the course of ahalf-hour, a precipitate formed in the solution. Methanol (1.5 mL) wasadded to dissolve the precipitate, and after an additional half-hour,the reaction was concentrated under reduced pressure to form a slurry.This was diluted with CHCl₃ (50 mL) and quenched with water (25 mL). Thesolution was extracted with CHCl₃ (3×50 mL) and ethyl acetate (3×50 mL)until all the formed solid was in solution. The combined organic layerswere washed with water (50 mL) and dried over brine followed by MgSO₄and then concentrated to give a yellow solid. The crude solid waspurified by chromatography (SiO₂, 5% MeOH/CHCl₃) to affordN-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-acetamide (118mg, 69%, m.p. 275° C., C₁₄H₁₇N₃O₂S, MS m/e 292 (M+H)⁺) as a light yellowsolid. HPLC-HI 100% at 3.95 min (YMC S5 ODS coulm 4.6×50 mm, 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

EXAMPLE 3 N-[5-(2-(5-t-butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-acetamide

A. Preparation ofN-[5-(2-(5-t-butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-acetamide

A solutionN-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]acetamide (67mg, 0.23 mmol) in ethyl acetate (10 mL) was added to a suspension ofpre-reduced Pd/C (10%) in ethyl acetate (5 mL). The reaction flask wasfitted with a hydrogen balloon and stirred for 24 hours. The reactionwas filtered, and the mixture was resubmitted to hydrogenation using thesame conditions as above. After an additional 24 hours, the reaction wasfiltered through a plug of celite, concentrated, and purified bychromatography (SiO₂, 5% MeOH/CHCl₃) to giveN-[5-(2-(5-t-butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-acetamide as awhite solid (3.5 mg, 5%, C₁₄H₁₉N₃O₂S, MS m/e 294 (M+H)⁺). HPLC-HI 91% at6.75 min (Zorbax SB C18 column 4.6×75 mm, 10-90% aqueous methanol over 8minutes containing 0.1% TFA, 2.5 mL/min, monitoring at 220 nm).

EXAMPLE 4N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide

A. Preparation of[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamic acidt-butyl ester

A sample of[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamic acidt-butyl ester could be prepared according to the methods described inExample 2.

B. Preparation of2-amino-5-[(E)-2-(5-t-butyl-oxazol-2-yl)-vinyl]-thiazole

To a suspension of[5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazo-2-yl]-carbamic acid t-butylester (1.5 g, 4.3 mmol) in tetrahydrofuran (30 mL) and water (3 mL) wasadded concentrated HCl(3 mL) dropwise. After addition was complete, themixture was heated at 60° C. overnight. The solution was concentrated invacuo to give a slurry, which was neutralized with saturated aqueousNaHCO₃ solution. The resulting solid was filtered and washed with waterand dried to give the free base (732 mg, 68%, C₁₂H₁₅N₃OS, MS m/e 250(M+H)⁺).

C. Preparation ofN-[5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide

To a solution of2-amino-5-[(E)-2-(5-t-butyl-oxazol-2-yl)-vinyl]-thiazole (20 mg, 0.08mmol) in dry CH₂Cl₂ (1 mL) was added dry DMF (0.1 mL) andN,N-diisopropylethylamine (28 μL, 0.16 mmol). The resulting solution wascooled to 0° C. and phenyl acetyl chloride (21 μL, 0.16 mmol) was addedvia syringe. The reaction mixture was allowed to warm to roomtemperature over two hours and then concentrated. Chromatography (SiO₂,5% MeOH/CH₂Cl₂) provided aN-[5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide asa mixture of Z and E isomers which were separated by reverse-phase HPLCto give the Z isomer (3 mg, 10%, MS m/e 368 (M+H)⁺) as a light yellowsolid, and the E isomer (3 mg, 10%, C₂₀H₂₁N₃O₂S, MS m/e 368 (M+H)⁺) as ayellow solid. (Z)-isomer: HPLC-HI 86% at 4.05 min (YMC S5 ODS column4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4mL/min, monitoring at 254 nm). (E) -isomer: HPLC-HI 84% at 4.18 min (YMCS5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 mL/min, monitoring at 254 nm).

EXAMPLE 5N-[5-(2-(5t-butyl-oxazol-2-yl)-ethynyl)-thiazol-2-yl]-acetamide

A. Preparation of 2-hydroxymethyl-5-t-butyloxazole

To a mixture of 2-chloromethyl-5-t-butyloxazole (13.0 g, 75.1 mmole),Cs₂CO₃ (36.0 g, 110.5 mmole) and acetic acid (10.5 mL, 192.6 mmole) inacetonitrile (120 ml) was heated at 65 deg C. overnight. All the solventwas removed under reduced pressure, the residue was partitioned betweenwater (60 mL) and EtOAc (100 mL) and the aqueous layer was extractedwith ethyl acetate (2×100 mL). The combined EtOAc solution was driedover MgSO₄ and concentrated to an oil.

The oil was dissolved in methanol (30 mL) and added with a solution ofNaOH (6.50 g, 163 mmole) in 30 ml of water, and stirred at roomtemperature overnight. MeOH was removed under reduced pressure, and theaqueous layer was extracted with EtOAc (3×80mL). The combined EtOAcsolution was dried over MgSO₄ and concentrated to give2-hydroxymethyl-5-t-butyloxazole as oil (11.76 g, 100%).

B. Preparation of 1,1-dibromo-2-(5′-t-butyloxazol-2-yl)ethylene

To a stirred solution of oxalyl chloride (45 mL, 90 mmole) at −78 deg C.under argon was added dropwise dimethyl sulfoxide (8.80 mL, 124 mmole).The reaction mixture was stirred at −78 deg C. for 10 min., and wastreated with a solution of 2-hydroxymethyl-5-t-butyloxazole (11.7 g,75.1 mmole) in anhydrous methylene chloride (30 mL) over 20 min. Themixture was stirred at this temperature for I hour, then triethylaminewas added slowly (31.0 mL, 222 mmole), during which the reaction mixturebecame a yellowish slurry. After stirring at −78 deg C. for 20 min, thereaction mixture was warmed to room temperature, added with methylenechloride (100 mL) and stirred for 1 hour. The solid was filtered off andwashed with EtOAc. The filtrate was washed with 5% aqueous citric acid(100 mL) and brine (50 mL), dried over MgSO₄. Concentration and columnchromatography (silica gel, EtOAc/hexane 1:4) afforded2-formyl-5-t-butyloxazole as a light yellow oil (10.1 g)

To a stirred solution of carbon tetrabromide (24.0 g, 72.4 mmole) inmethylene chloride (200 mL) at 5-10 deg C. under argon atmosphere wasadded triphenylphosphine (37.0 g, 141 mmole) in portions. The reactionmixture was stirred for 5 min and treated with a solution of2-formyl-5-t-butyloxazole in methylene chloride (60 mL). The reactionmixture was stirred at room temperature for 2 hours, while a white solidprecipitated out of the solution. The solid was filtered off, thefiltrate concentrated and purified (silica gel, EtOAc/hexane 1:4) togive 1,1-dibromo-2-(5-t-butyl-oxazol-2-yl)ethylene as a pale solid (9.13g, 39 %).

C. Preparation ofN-[5-(2-(5-t-butyl-oxazol-2-yl)-acetelenyl)-thiazol-2-yl]-acetamide

To a stirred solution of 1,1-dibromo-2-(5-t-butyl-oxazol-2-yl)ethylene(6.0 g, 19 mmole) in anhydrous THF (80 mL) at −78 deg C. under argonatmosphere. was added with 1.6 M n-butyllithium (32 mL, 51 mmole) inhexane dropwise over 20 min., the reaction mixture, stirred at −78 degC. for 30 min and treated with tributyltin chloride (5.5 mL, 20 mmole).The reaction mixture was stirred for 30 min, warmed to 0 deg C., stirredat 0 deg C. for 30 min, and then at room temperature for 45 min. Themixture was passed through a short column of silica gel (deactivatedwith 2% triethylamine in hexane), and eluted with 10% EtOAc indichloromethane to obtain crude product of1-tributylstannyl-2-(5-t-butyl-oxazol-2-yl)acetylene as a brown oil(9.10 g).

To a stirred solution of above crude product of tin compound under argonand 2-N-acetylamino-5-iodothiazole (4.65 g, 17.3 mmole) in anhydrous THF(100 mL) at room temperature was added solidtris(dibenzylideneacetone)dipalladium(0) (1.40 g, 1.53 mmole), followedby trifurylphosphine (2.0 g, 8.6 mmole). The reaction mixture wasstirred at room temperature for 10 min., then heated at 65 deg C. for2.5 hours. The catalyst was filtered off, the filtrate concentrated andpurified by column silica gel chromatography (EtOAc/hexane 1:2 to 2:1)to give N-[5-(2-(5-t-butyl-oxazol-2-yl)-ethynyl)-thiazol-2-yl]-acetamideas a light brown solid (2.60 g, 46%). C14H15N3O2S, MS m/e 290 (M+H)+.HPLC-HI 100% at 4.02 min (YMC S5 ODS column 4.6×50,mm, 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm).

EXAMPLE 6N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-aminopyridine

Preparation ofN-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-aminopyridine

To a solution of 2-aminopyridine (238 mg, 2.56 mmol) in THF (8 mL) underargon was added sodium hydride (100 mg of 60% oil dispersion, 2.5 mmol)and the reaction stirred at 60 deg C. for 15 minutes, cooled to roomtemperature and2-bromo-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazole] (200 mg, 0.64mmol) was added in one portion. The reaction mixture was stirred for 20minutes, quenched with hydrochloric acid, washed with water andextracted with ethyl acetate. The organic layers were separated andconcentrated to give a crude product which was heated with ethylacetate: hexanes (1:1), cooled, filtered, and dried under vacuum to givethe desired product. C₁₇H₁₈N₄OS, MS m/e 327 (M+H)⁺. HPLC-HI 100% at 4.24min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Using the procedures described herein or by modification of theprocedures described herein as known to one of ordinary skill in theart, additional compounds as shown in FIGS. 1-20 have been prepared.

We claim:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof wherein: R¹=COR³;R³=heteroarylalkyl;

R⁴=alkyl with two or more carbon atoms, cycloalkyl, heterocycloalkyl,cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, or R⁹; R⁵, R⁶, R⁷, and R⁸=independently H, alkyl,cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, halo, hydroxy, alkoxy,amino, NR¹²R¹³, thio, or alkylthio with the proviso that only one suchheteroatom group is bonded to any one carbon atom;

R¹⁰ and R¹¹=independently H, alkyl, cycloalkyl, heterocycloalkyl,cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, halo, hydroxy, alkoxy, alkylcarbonyloxy, carboxy,alkyloxycarbonyl, amino, NR¹⁵R¹⁶, carbamoyl, ureido, thio, or alkylthio;and R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶=independently H, alkyl, cycloalkyl,heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl.
 2. The compound as recited inclaim 1, wherein: Y=optionally substituted alkenyl, alkynyl, or any 2adjacent carbon atoms of a cycloalkyl ring; R⁴=alkyl with two or morecarbon atoms, aryl, heteroaryl, or R⁹; R⁵, R⁶, R⁷, and R⁸=independentlyH or alkyl; where Z=O; and R¹⁰ and R¹¹=independently H, alkyl orcycloalkyl.
 3. The compound as recited in claim 1, wherein: n=0 or 1;m=1 or Y=optionally substituted alkenyl; R⁴=R⁹; R⁵, R⁶, R⁷, andR⁸=independently H or alkyl; where Z=O; and R¹⁰ and R¹¹=independently H,alkyl or cycloalkyl.
 4. The compound as recited in claim 1, wherein:

R⁵, R⁶, R⁷ and R⁸=independently H or alkyl; R⁴=R⁹; where Z=O; R¹⁰=alkylor cycloalkyl; and R¹¹=H.
 5. The compound as recited in claim 1,wherein:

R⁴=R⁹; R⁵, R⁶, R⁷, and R⁸=independently H or alkyl; where Z=O; R¹⁰=alkylor cycloalkyl; and R¹¹=H.
 6. The compound as recited in claim 1,wherein: where n=0 or 1; m=1; Y=optionally substituted alkenyl; and R⁵,R⁶, R⁷ and R⁸=independently H or alkyl.
 7. A compound selected from thegroup consisting of:N-[(E)-5-(2-(5-Isopropyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-pyridin-3-yl-acetamide;N-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-pyridin-3-yl-acetamide;N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-pyridin-3-yl-acetamide;N-{(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(3H-imidazol-4-yl)-acetamide;N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(imidazol-1-yl)-acetamide;N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(1-methyl-imidazol-4-yl)-acetamide;N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3-[imidazol-4-yl)-2-(N′-acetylamino)-propionamide;N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-[3-(1-methyl-benzimidazol-2-yl)]-propionamide;t-butoxyacetylamino)-propionamide;(S)-N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3[(1-methyl-imidazol-4-yl)]-2-(N-t-butoxyacetylamino)-propionamide;(S)-N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3-(imidazol-4-yl)-2-amino-propionamide;(S)-N-[(E)-5-(3-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-3-(1-methyl-imidazol-5-yl)-2-amino-propionamide;N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(2-methylpyridin-3-yl)-acetamide;N-[(Z)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(imidazol-1-yl)-acetamide;N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(1-oxy-pyridin-3-yl)-acetamide;N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(pyridin-3-yl)-propionamide;N-{(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(2-methyl-pyridin-3-yl)-propionamide;3-(N-{(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-carbamoyl-methyl-1-methyl-pyridiniumiodide;N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-imidazol-1-yl-acetamide;N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-pyrazol-1-yl-acetamide;N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(4,5-dichloro-imidazol-1-yl)acetamide;N-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(4,5-dicyano-imidazol-1-yl)acetamide;andN-[(E)-5-(2-(5-t-Butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-2-(2-methyl-imidazol-1-yl)-acetamide.8. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 9. A pharmaceutical compositioncomprising a compound of claim 1 in combination with pharmaceuticallyacceptable carrier and an anti-cancer agent formulated as a fixed dose.